A. Specific Aims The ultimate goal of our research is to elucidate the pathways underlying the altered neurobiology of Down syndrome, focusing on neocortex and hippocampus. The past decade has focused on sequencing chromosome 21, evaluating gene expression in cell lines and trisomic mouse models, identifying signaling pathways involving chromosome 21 genes, and looking at the effects of segmental trisomy in mouse, on cellular, neuroanatomic and behavioral phenotypes. The results of these studies may lead to new approaches to ameliorate the deleterious effects of these genes on development and cognition in DS. Systems Medicine: Our work provides insights that support a fundamental change in the approach to mental retardation, from orientation on single components to the use of a broader, neural systems based approach to identify common pathways that may underly a spectrum of MR in humans. Beginning with humans with partial trisomy for 21, we identified regions and then single genes likely involved in MR in DS and then generated single gene mouse models, relating findings to humans with aneuploidy for 21. In the current year, we have identified expression patterns and abnormalities in the brains of these mice (and in our other chromosome 21 models), at the level of brain structure, the dendritic tree, dendritic spine, behavior and cell biology (additional model), and have begun to generate fly models of the same subset of DS genes, and to investigate their gene expression in non-human primates. Combining the data from DS and mouse models suggests that disturbances of a smaller number of common developmental pathways may underly a broader spectrum of MR and focus models in which to test these. It is important to note that the recent report of a mouse model generated with sequences originating from human (not mouse) chromosome 21 (Fisher and "^Progress has been made in all aims, with exciting accomplishments including the knock-out mouse for dscam, the establishment of fly models for DS/ chromosome 21 genes, the beautiful Golgi Staining for dendrites, spines and neuronal systems altered in the Pcp4/ PEP19 transgenic, the identification of meso-limbic system expression of Pcp4/PEP19Jn mouse, and finally, emerging from this findings produced by this proposal, but beyond the funded scope, expression in limbic system of Macaque fasicularis (monkey), and preliminary evidence in DS for abnormal specific neuronal populations in human prefrontal cortex. Accomplishments and plans are listed under each aim.